Cathepsin S inhibitor prevents autoantigen presentation and autoimmunity

Abstract

The cysteine endoprotease cathepsin S mediates degradation of the MHC class II invariant chain Ii in human and mouse antigen-presenting cells. Studies described here examine the functional significance of cathepsin S inhibition on autoantigen presentation and organ-specific autoimmune diseases in a murine model for Sjögren syndrome. Specific inhibitor of cathepsin S (Clik60) in vitro markedly impaired presentation of an organ-specific autoantigen, 120-kDa α-fodrin, by interfering with MHC class II-peptide binding. Autoantigen-specific T cell responses were significantly and dose-dependently inhibited by incubation with Clik60, but not with inhibitor s of cathepsin B or L. Clik60 treatment of mouse salivary gland cells selectively inhibited autopeptide-bound class II molecules. Moreover, the treatment with Clik60 in vivo profoundly blocked lymphocytic infiltration into the salivary and lacrimal glands, abrogated a rise in serum autoantibody production, and led to recovery from autoimmune manifestations. Thus, inhibition of cathepsin S in vivo alters autoantigen presentation and development of organ-specific autoimmunity. These data identify selective inhibition of cysteine protease cathepsin S as a potential therapeutic strategy for autoimmune disease processes.

Anti-Inflammatory Effects of Rebamipide Eyedrop Administration on Ocular Lesions in a Murine Model of Primary Sjögren's Syndrome

“…On the other hand, there are no differences in body weight, gross pelage aspect, reproductive capacity between control and thymectomized NFS/ sld mice. As for immunological aspects such as decreased T cell number, enhanced Th1-type cytokine production, and autoantibody production in addition to autoimmune lesions in salivary and lacrimal glands were observed in the thymectomized mice [25]–[27].…”

“…In contrast, thymectomized NFS/ sld mice have been established as a model of primary SS [10]. As inflammatory lesions in this model are localized in salivary and lacrimal glands, resembling human primary SS, and immune phenotypes and responses including cytokine profile, autoantibody production, or antigen-specific T cell responses are similar to those of human SS, this animal model has been used for analyzing the pathogenesis of SS and establishing new therapeutic strategies [25]–[27]. In addition, autoimmune lesions have an earlier onset in young mice (aged 6–8 weeks), with the frequency of onset being almost 100%.…”

Cathepsin S inhibition combines control of systemic and peripheral pathomechanisms of autoimmune tissue injury

“…In addition, Cat-S limits auto-reactive CD4 T cell escape from thymic selection by degrading auto-antigenic peptides 14 , hence, there is a robust rationale for Cat-S being a mediator of autoimmunity. Lack of Cat-S or Cat-S inhibition was shown to suppress autoimmunity in a number of animal models such as autoimmune encephalitis 15 , collagen-related autoimmunity 15 , Sjögren’s syndrome 16 or SLE 17 .…”

Pathological Analysis of Ocular Lesions in a Murine Model of Sjögren’s Syndrome

“…The pathogenesis and molecular mechanisms of SS have been investigated in various animal models of SS [5], including a thymectomized neonatal NFS/ sublingual gland ( sld ) mutant mouse model, which we developed to study SS and the therapeutic effects of several reagents on its autoimmune lesions [6,7,8,9,10]. The detailed ocular lesions in the eyeball, cornea, iris, and lacrimal gland lesions in the mouse models are not fully understood due to the complicated anatomy and small structures.…”